EP0259168B1 - New water-soluble salts of thionapthene-2-carboxylic acid - Google Patents
New water-soluble salts of thionapthene-2-carboxylic acid Download PDFInfo
- Publication number
- EP0259168B1 EP0259168B1 EP87307807A EP87307807A EP0259168B1 EP 0259168 B1 EP0259168 B1 EP 0259168B1 EP 87307807 A EP87307807 A EP 87307807A EP 87307807 A EP87307807 A EP 87307807A EP 0259168 B1 EP0259168 B1 EP 0259168B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- salt
- tnca
- lysine
- carboxylic acid
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- DYSJMQABFPKAQM-UHFFFAOYSA-N 1-benzothiophene-2-carboxylic acid Chemical class C1=CC=C2SC(C(=O)O)=CC2=C1 DYSJMQABFPKAQM-UHFFFAOYSA-N 0.000 title claims description 52
- 150000003839 salts Chemical class 0.000 title description 29
- 239000000243 solution Substances 0.000 claims description 19
- 239000004472 Lysine Substances 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 11
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000004475 Arginine Substances 0.000 claims description 6
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 6
- 150000001483 arginine derivatives Chemical class 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 4
- 239000012736 aqueous medium Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 125000003158 alcohol group Chemical group 0.000 claims 1
- 238000011065 in-situ storage Methods 0.000 claims 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 claims 1
- 239000011973 solid acid Substances 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 15
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- 229910052791 calcium Inorganic materials 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
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- 230000000694 effects Effects 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
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- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 5
- 150000003863 ammonium salts Chemical class 0.000 description 5
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- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 3
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- NJYFRQQXXXRJHK-UHFFFAOYSA-N (4-aminophenyl) thiocyanate Chemical compound NC1=CC=C(SC#N)C=C1 NJYFRQQXXXRJHK-UHFFFAOYSA-N 0.000 description 2
- 206010065687 Bone loss Diseases 0.000 description 2
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- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- HCUARRIEZVDMPT-UHFFFAOYSA-N Indole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 2
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- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 1
- OIRWVCFHDZVOIC-ZSCHJXSPSA-N 1-benzothiophene-2-carboxylic acid;(2s)-2,6-diaminohexanoic acid Chemical compound NCCCC[C@H](N)C(O)=O.C1=CC=C2SC(C(=O)O)=CC2=C1 OIRWVCFHDZVOIC-ZSCHJXSPSA-N 0.000 description 1
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- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- GRWKNBPOGBTZMN-UHFFFAOYSA-N 2-benzyl-3-phenylpropane-1,2-diamine Chemical compound C=1C=CC=CC=1CC(N)(CN)CC1=CC=CC=C1 GRWKNBPOGBTZMN-UHFFFAOYSA-N 0.000 description 1
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- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000008136 water-miscible vehicle Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
Definitions
- This invention relates to thionapthene-2-carboxylic acid (TNCA) water-soluble salts (TNSA) (Also called Benzo(b)thiophene-2-carboxylic acid salts), and processes of making and using these compounds.
- TNCA thionapthene-2-carboxylic acid
- TNSA water-soluble salts
- Osteoporosis is a common and progressive condition occurring in adults which results in a decrease in bone throughout the body. This loss includes the mineral portion of the bone, which is a calcium phosphate material called "hydroxyapatite", as well as the matrix, which is a protein called "collagen”. Osteoporosis may begin in early adulthood and progress, inexorably, to middle age and old age with manifestations running the gamut of moderate to severe pain along with X-ray evidence of bone loss and/or deformation to eventual brittleness which we see evidenced, for example, in older people who so easily break a hip bone from a simple, and seemingly not dangerous, fall. It has been stated that osteoporosis is the most common cause of fractures in people over the age of 65.
- thionaphthene-2-carboxylic acid thionaphthene-3-carboxylic acid
- thionaphthene-4-carboxylic acid dibenzothiophene-4-carboxylic acid
- thioxanthene-9-one-4-carboxylic acid indole-2-carboxylic acid.
- the compounds are compared to thyrocalcitonin (TCT), the latter, a bond-remodeling hormone which is capable of reducing bone resorption rates.
- TCT thyrocalcitonin
- the effectiveness of any bone resorption modifying agent is determined by measuring the effect on the production of cyclic adenosine-3 ⁇ 5 ⁇ -monophosphate (c-AMP) using the methods of Rodan et al, J.B.C. Vol 429, page 306, 1974; Rodan et al, Science, Vol. 189, page 467, 1975.
- the activity shown by the free acid compounds covered by the disclosure of the aforementioned patents ranges from slightly more than half as effective to twice as effective as TCT in stimulating the production of c-AMP.
- the "pharmaceutically acceptable salts include the non-toxic metallic salts such as sodium, potassium, calcium and aluminum, the ammonium salt and substitued ammonium salts, e.g., salts of such nontoxic amines as trialkylamines including thiethylamine "--(presumably triethylamine is intended)--" L-lysine, procaine, dibenzylamine, N-benzyl-beta phenylethylamine, L-ephenamine-N,N ⁇ dibenzylethylenediamine, N-(lower) alklypiperidine, e.g., N-ethylpiperidine", but no specific salt is given.
- non-toxic metallic salts such as sodium, potassium, calcium and aluminum
- the ammonium salt and substitued ammonium salts substitued ammonium salts, e.g., salts of such nontoxic amines as trialkylamines including thiethylamine "--(presumably tri
- Example 5 of each patent benzo(b)thiophene-2-carboxylic acid was used for 3 days (1 mg/day by subcutaneous (S.C.) injection.
- Example 6 the dose was reduced to 200 ug/day and in Example 7, the drug was injected for 10 days (S.C. 1 mg/day).
- mice In other studies it has been found that in acute toxicities in rats and monkeys, using TNCA in gum tragacanth, the oral LD50 in mice is 3.6 g/kg whereas when injected subcutaneously, the LD50 in mice is 1.45 g/Kg, indicating a low response level to the orally ingested drug.
- the present invention provides new salts of benzo(b)thiophene-2-carboxylic which are readily prepared in high yields, which are particularly free of irritating side effects in the stomach as well as other untoward effects when taken orally, and which give rise to rapid and clinically-response-effective blood levels via the oral route.
- the LD50 of the water-soluble salts of this invention and particularly the L-lysine salt when given orally is almost equivalent to that obtained when administered intraperitoneally.
- the specific salts with which this invention is concerned are the L-lysine salt and the L-arginine salt.
- these salts are easily prepared, readily isolated, obtainable in good yields, and water-soluble.
- other salts which would suggest themselves, namely, the sodium salt, potassium salt, glycine salt, L-alanine salt, L-proline salt and even the triethylamine salt.
- a salt as the potassium and sodium salts have proven difficult to prepare and when made are mainly insoluble in water.
- ammonium salt (not of the present invention) is simply and conveniently made by merely mixing even dilute ammonium hydroxide solutions with the solid free acid (benzo(b)thiophene-2-carboxylic acid) and evaporating the water to isolate the ammonium salt
- solid TNCA when mixed into aqueous caustic soda solutions is totally unaffected and unreactive to form the sodium salt; this is true with 8% (2N) and with 20%, 40%, and 60% aqueous solutions. This is also the case when one uses aqueous sodium carbonate.
- the pK of the TNCA is 3.4, this action is quite strange.
- the L-lysine salt is also made in the same simple and efficacious manner as the ammonium salt, again by the incremental addition of the TNCA to an aqueous solution of L-lysine.
- a suitable solvent such as methanol
- the sodium salt is produced only when one utilizes sodium ethoxide in methanol or sodium hydroxide in a mixture of alcohol and water.
- the formation of the sodium salt was demonstrated by means of infra-red spectroscopy and also the fact that it does not melt.
- the potassium salt could not be formed by treatment with aqueous potassium hydroxide.
- the potassium salt of TNCA is formed when excess potassium hydroxide and TNCA are added to a warm solution of methanol containing a small amount of water.
- TNCA as an acid in high concentrations, causes gastric irritation, resulting in vomiting and bleeding.
- TNCA lysine salt acts as an effective buffer, hence prevents the adverse effects associated with gastric irritation.
- TNCA is poorly absorbed from the gastrointestinal tracts; as mentioned earlier, the oral LD50 is 3.6 gm/Kg., whereas by injection, this value is only 1.45 g/Kg.
- the oral dose of the TNCA lysine salt is roughly 1.5 g/Kg and, by injection, is not significantly different (approximately 1.3 g/Kg).
- a solution is prepared by mixing a solution of 447 mg of triethanolamine (0.003 mole) in 15 ml of methanol with another solution of 537 mg (0.003 mole) benzo(b)-thiophene-2-carboxylic acid (TNCA) in 5 ml of methanol.
- a 5% aqueous solution of the salt has a pH of 6.77.
- Sodium salt of TNCA 108 mg (0.002 mole) of sodium ethoxide in 6 ml methanol is mixed with 358 mg (0.002 mole) of TNCA in 10 ml of methanol. 321 mg of a white water-insoluble salt is obtained on removal of the methanol from the almost clear solution. The solid does not melt below 300°C and the IR spectrum clearly indicates the presence of a salt.
- Particularly useful for patient use are pharmaceutically acceptable liquid dosage forms incorporating TNCA and they may be prepared by utilizing the teachings exemplified above regarding the formation of salts of TNCA with TNCA as the acid.
- the base is chosen from the class of lysine and arginine.
- Liquid dosage forms may be prepared either by the dissolution of the isolated salt into water, by the dissolution of TNCA into an aqueous solution containing lysine or arginine salts, or by the simultaneous dissolution of TNCA and the free base into an aqueous medium.
- one ml of the solution may contain 15-1000 mg of TNCA, as the salt of lysine and/or arginine. Also contained in the solution may be sodium chloride for the purpose of achieving isotonicity, sodium hydroxide for pH adjustment (preferably 6 to 8), and phosphate buffer to maintain pH. Also included may be a preservative, a humectant, a flavor, and a color.
- a pharmaceutically acceptable liquid oral dosage form containing salts of TNCA may also be prepared as a combination solution/suspension, in which a portion of the TNCA salt is dissolved and the remainder is suspended.
- the preparation may contain 15-1000 mg of TNCA per ml as the salts of lysine or arginine.
- the body of the preparation may consist of distilled deionized water into which a portion of the salt is dissolved, and a water-miscible vehicle which is used as the supporting medium for the suspended TNCA salt.
- This formulation would also contain sodium chloride, sodium hydroxide, and a phosphate buffer as well as a suspending agent, a flavor, and a color.
- Another pharmaceutically acceptable liquid oral dosage form containing TNCA may also be prepared as an emulsion.
- the preparation may contain 15-1000 mg of TNCA per ml as the salts of lysine or arginine.
- the body of the preparation may consist of distilled deionized water and a vegetable oil properly emulsified with an emulsifying agent such as lecithin, pluronics, tweens, brijs, or arlacels, etc., as needed to produce a stable W/O emulsion of the water solution of the TNCA salt in the external oil phase.
- an emulsifying agent such as lecithin, pluronics, tweens, brijs, or arlacels, etc.
- Also included may be sodium chloride, sodium hydroxide, phosphate buffer, preservative, humectant, flavor and color.
- Liquid oral dosage forms may offer advantages in certain patients and in certain applications. Patients unable to swallow large solid dosage forms would be particularly good candidates for a liquid dosage form. Liquid dosage forms may also allow larger amounts of drug to be administered in a manner that promotes patient compliance.
- a liquid dosage form may be used parenterally (by injection) either by I.V., S.C. or I.M.
- one ml of solution may contain, in part, 15-1000 mg of TNCA as the salt of lysine or arginine.
- a salt such as sodium chloride for the purpose of achieving isotonicity; sodium hydroxide for adjustment of pH as needed (preferably to within the range 6 - 8); phosphate buffer; a preservative if needed; and U.S.P. Water For Injection.
- Oral Solution TNCA 600 mg l-arginine 586.5 mg sodium chloride, U.S.P. 2.0 mg sodium hydroxide, U.S.P. 0.2 mg potassium sorbate, U.S.P. 0.05 mg phosphate buffer (pH 7.0) 3.0 ml glycerine, U.S.P. 100 mg saccharin sodium, U.S.P. 0.5 mg natural strawberry flavor 0.05 ml FD&C Red #40 0.0001mg distilled deionized water q.s.a.d. 10.0 ml
Description
- This invention relates to thionapthene-2-carboxylic acid (TNCA) water-soluble salts (TNSA) (Also called Benzo(b)thiophene-2-carboxylic acid salts), and processes of making and using these compounds.
- Osteoporosis is a common and progressive condition occurring in adults which results in a decrease in bone throughout the body. This loss includes the mineral portion of the bone, which is a calcium phosphate material called "hydroxyapatite", as well as the matrix, which is a protein called "collagen". Osteoporosis may begin in early adulthood and progress, inexorably, to middle age and old age with manifestations running the gamut of moderate to severe pain along with X-ray evidence of bone loss and/or deformation to eventual brittleness which we see evidenced, for example, in older people who so easily break a hip bone from a simple, and seemingly not dangerous, fall. It has been stated that osteoporosis is the most common cause of fractures in people over the age of 65.
- While the causes of osteoporosis are not well understood and, in many cases quite obscure, it is believed that there is an imbalance between bone production and bone resorption (i.e., bone breakdown).
- During the life of an animal, new bone is continuously being formed and old bone resorbed. In osteoporosis, resorption exceeds bone formation.
- Present methods for treating osteoporosis are far from satisfactory. Such treatments include the administration of calcium salts, fluorides, calcitonin, estrogens, Vitamin D, and anabolic agents, among others. Anabolic agents and estrogen therapy have been the therapy of choice for osteoporosis in post-menopausal women. Such treatments appear to entail an increased risk of uterine and breast cancer. Other treatments still remain to be proven including the Physical Therapy approach.
- Among the newer approaches to the treatment of osteoporosis has been the use of materials with hypocalcemic activity, i.e., lowering of the serum calcium, which is believed to be related to and indicative of a decrease in the rate of bone resorption. Calcitonin, mithramycin (an antibiotic) and certain phosphonates are representative hypocalcemic agents, but adverse effects and lack of effectiveness in bone-loss prevention associated with the use of such agents, make continued research necessary.
- In recent U.S. Patents 4,101,668 (issued July 18, 1978), 4,125,621 (issued November 14, 1978) and 4,185,108 (issued January 22, 1980), all three having as inventors C. M. Samour and J. A. Vida, there are disclosed a wide variety of benzo-heterocyclic compounds for use as antiosteoporotic agents. Among the specific compounds described are thionaphthene-2-carboxylic acid, thionaphthene-3-carboxylic acid, thionaphthene-4-carboxylic acid, dibenzothiophene-4-carboxylic acid, thioxanthene-9-one-4-carboxylic acid and indole-2-carboxylic acid.
- The compounds are compared to thyrocalcitonin (TCT), the latter, a bond-remodeling hormone which is capable of reducing bone resorption rates. In the patented disclosures, the effectiveness of any bone resorption modifying agent is determined by measuring the effect on the production of cyclic adenosine-3ʹ5ʹ-monophosphate (c-AMP) using the methods of Rodan et al, J.B.C. Vol 429, page 306, 1974; Rodan et al, Science, Vol. 189, page 467, 1975. In the comparison, the activity shown by the free acid compounds covered by the disclosure of the aforementioned patents ranges from slightly more than half as effective to twice as effective as TCT in stimulating the production of c-AMP.
- The U.S. Patents (to Samour et al) 4,101,668, 4,125,621 and 4,185,108 mentioned in the "Background" to the present invention constitute the only significant Prior Art to which we are aware.
- In the patents, mention is made that the "pharmaceutically acceptable salts include the non-toxic metallic salts such as sodium, potassium, calcium and aluminum, the ammonium salt and substitued ammonium salts, e.g., salts of such nontoxic amines as trialkylamines including thiethylamine "--(presumably triethylamine is intended)--" L-lysine, procaine, dibenzylamine, N-benzyl-beta phenylethylamine, L-ephenamine-N,Nʹ dibenzylethylenediamine, N-(lower) alklypiperidine, e.g., N-ethylpiperidine", but no specific salt is given. The studies shown in the patent were done in vitro and in vivo but the latter were conducted by injecting the drug. In Example 5 of each patent, benzo(b)thiophene-2-carboxylic acid was used for 3 days (1 mg/day by subcutaneous (S.C.) injection. In Example 6 the dose was reduced to 200 ug/day and in Example 7, the drug was injected for 10 days (S.C. 1 mg/day).
- In other studies it has been found that in acute toxicities in rats and monkeys, using TNCA in gum tragacanth, the oral LD₅₀ in mice is 3.6 g/kg whereas when injected subcutaneously, the LD₅₀ in mice is 1.45 g/Kg, indicating a low response level to the orally ingested drug.
- The present invention provides new salts of benzo(b)thiophene-2-carboxylic which are readily prepared in high yields, which are particularly free of irritating side effects in the stomach as well as other untoward effects when taken orally, and which give rise to rapid and clinically-response-effective blood levels via the oral route. The LD₅₀ of the water-soluble salts of this invention and particularly the L-lysine salt when given orally is almost equivalent to that obtained when administered intraperitoneally.
- The specific salts with which this invention is concerned are the L-lysine salt and the L-arginine salt.
- Surprisingly, these salts are easily prepared, readily isolated, obtainable in good yields, and water-soluble. This is to be contrasted with other salts which would suggest themselves, namely, the sodium salt, potassium salt, glycine salt, L-alanine salt, L-proline salt and even the triethylamine salt. As a matter of fact so suggestive a salt as the potassium and sodium salts have proven difficult to prepare and when made are mainly insoluble in water. In this regard, it is to be noted that while the ammonium salt (not of the present invention) is simply and conveniently made by merely mixing even dilute ammonium hydroxide solutions with the solid free acid (benzo(b)thiophene-2-carboxylic acid) and evaporating the water to isolate the ammonium salt, solid TNCA when mixed into aqueous caustic soda solutions is totally unaffected and unreactive to form the sodium salt; this is true with 8% (2N) and with 20%, 40%, and 60% aqueous solutions. This is also the case when one uses aqueous sodium carbonate. Considering that the pK of the TNCA is 3.4, this action is quite strange. The L-lysine salt is also made in the same simple and efficacious manner as the ammonium salt, again by the incremental addition of the TNCA to an aqueous solution of L-lysine. The use of solutions of both reactants in a suitable solvent such as methanol may be used with facility since the TNCA compound is soluble in methanol. In contrast, the sodium salt is produced only when one utilizes sodium ethoxide in methanol or sodium hydroxide in a mixture of alcohol and water. The formation of the sodium salt was demonstrated by means of infra-red spectroscopy and also the fact that it does not melt. Similarly, the potassium salt could not be formed by treatment with aqueous potassium hydroxide. However, the potassium salt of TNCA is formed when excess potassium hydroxide and TNCA are added to a warm solution of methanol containing a small amount of water.
- The utility of the salts, in a clinical treating sense, is equivalent to TNCA itself but they are far more useful, practically, for the reasons of amelioration of side effects and the high blood levels available via the oral route.
- As examples, TNCA, as an acid in high concentrations, causes gastric irritation, resulting in vomiting and bleeding. On the other hand, TNCA lysine salt acts as an effective buffer, hence prevents the adverse effects associated with gastric irritation.
- More importantly, TNCA is poorly absorbed from the gastrointestinal tracts; as mentioned earlier, the oral LD₅₀ is 3.6 gm/Kg., whereas by injection, this value is only 1.45 g/Kg. In marked contrast, the oral dose of the TNCA lysine salt is roughly 1.5 g/Kg and, by injection, is not significantly different (approximately 1.3 g/Kg). This finding that TNCA lysine salt is equally effective when given orally or by injection, indicates that the lysine salt, in contrast to TNCA, is readily absorbed following oral administration.
- The following examples will serve to illustrate the present invention without being deemed limitative thereof. Parts, when used, are by weight, unless otherwise indicated.
- Preparation of Benzo(b)thiophene-2-carboxylic acid L-Lysine salt:
95.02 g (0.65 mole) of L-lysine is dissolved in 637 ml. of water. To this solution is added, in small portions, 115.83 g (0.65 mole) of TNCA (m.p. 237-238°C) and the reaction mixture is stirred at 50°C for one hour. The mixture is then filtered and the water is removed from the filtrate to give a pinkish white solid of the above formula and with a melting point of 240-242°C. The salt is highly (70%) water-soluble. A 5% aqueous solution of the salt has a pH of 5.75. It is insoluble in methyl alcohol, ethyl alcohol and toluene. - A solution is prepared by mixing a solution of 447 mg of triethanolamine (0.003 mole) in 15 ml of methanol with another solution of 537 mg (0.003 mole) benzo(b)-thiophene-2-carboxylic acid (TNCA) in 5 ml of methanol. The solution is filtered and the solvent is removed from the filtrate to give 850 mg of a white water-soluble solid, m.p. = 144-148°C. A 5% aqueous solution of the salt has a pH of 6.77.
- Preparation of the Arginine salt of TNCA:
To a solution of 2.97 g (0.016 mole) of L-arginine in 18 ml of water is added, while being stirred, 3 g (0.016 mole) solid TNCA. The mixture is stirred at 40°C until all TNCA dissolves. The water was removed in vacuum. 5.6 g of a white, water-soluble solid, m.p. = 55°-60°C., is obtained. A 5% aqueous solution of the salt has a pH of 5.8. The salt is also soluble in methanol and ethanol. - Preparation of the Sodium salt of TNCA:
108 mg (0.002 mole) of sodium ethoxide in 6 ml methanol is mixed with 358 mg (0.002 mole) of TNCA in 10 ml of methanol. 321 mg of a white water-insoluble salt is obtained on removal of the methanol from the almost clear solution. The solid does not melt below 300°C and the IR spectrum clearly indicates the presence of a salt. - Following the procedure of Example 6, 203 mg (0.002 mole) of triethylamine is dissolved in 4 ml of methanol and mixed with 358 mg (0.002 mole) of TNCA in 10 ml. of methanol. A water-insoluble liquid results.
- Following the procedure of Example 1, L-alanine, L-glycine, and L-proline are used, in equivalent amounts in place of L-lysine. No water-soluble reaction product is formed.
- The following tables (Experiments I and II) illustrate the effectiveness of the present invention in reducing the blood calcium levels of rats made hypercalcemic by the injection of Leydig-cell carcinoma-tumor material. For details of the methodology employed in these studies, see: Johannesson et al., Endocrinology 117/4: 1508-1511 (1985). Normal calcium blood levels are in the range of 9-10 mg/dL.
-
Table I (Experiment 1) Measure Group N Mean S.D. Initial Control 5 11.22 1.68 Calcium 195 mg/kg 8 12.28 1.71 Levels 292 mg/kg 9 13.31 3.32 Final Control 5 17.38 3.71 Calcium 195 mg/kg 8 14.85 3.56 Levels 292 mg/kg 9 11.54 2.54 Table II (Experiment 2) Measure Group N Mean S.D. Initial Control 6 15.17 2.26 Calcium 195 mg/kg 6 14.07 2.33 292 mg/kg 6 14.68 2.56 389 mg/kg 10 13.80 2.70 Final Control 6 18.03 2.14 Calcium 195 mg/kg 6 13.27 2.07 Levels 292 mg/kg 6 11.00 1.30 389 mg/kg 8 10.16 0.49 - The data in Tables I & II show that the initial serum concentrations of calcium are considerably higher than normal for the rat, ranging from 11.22 to 13.31 mg/dL (mg per deciliter) in Experiment 1 and from 13.80 to 15.17 mg/dL in Experiment 2. In the table, n = number of rats evaluated at each dosage and in controls while S.D. = standard deviation. These higher initial values reflect Leydig cell-induced hypercalcemia. Data for final calcium levels show the decreases in calcium levels produced following administration of the lysine salt of TNCA. Such decreases are clearly dose-related in both experiments, dropping from control values of 17.38 to 11.54 in Experiment 1, and from 18.03 to 10.16 in Experiment 2, corresponding to doses of 292 mg/Kg and 389 mg/Kg, respectively. It is noteworthy that the serum calcium levels following treatment with the lysine salt of TNCA returned to pretreatment levels, but not to below normal values, i.e., not below calcium concentrations present before the development of Leydig cell tumors. This indicates that the lysine salt of TNCA is anti-hypercalcemic, rather than hypocalcemic. The distinction is important since the objective of therapy with this drug is to lower calcium significantly, but not to levels that would cause the adverse effects of hypocalcemia.
- Particularly useful for patient use are pharmaceutically acceptable liquid dosage forms incorporating TNCA and they may be prepared by utilizing the teachings exemplified above regarding the formation of salts of TNCA with TNCA as the acid. The base is chosen from the class of lysine and arginine.
- Liquid dosage forms may be prepared either by the dissolution of the isolated salt into water, by the dissolution of TNCA into an aqueous solution containing lysine or arginine salts, or by the simultaneous dissolution of TNCA and the free base into an aqueous medium.
- The following are suggested dosage formulations:
In the liquid oral dosage form, one ml of the solution may contain 15-1000 mg of TNCA, as the salt of lysine and/or arginine. Also contained in the solution may be sodium chloride for the purpose of achieving isotonicity, sodium hydroxide for pH adjustment (preferably 6 to 8), and phosphate buffer to maintain pH. Also included may be a preservative, a humectant, a flavor, and a color. - A pharmaceutically acceptable liquid oral dosage form containing salts of TNCA may also be prepared as a combination solution/suspension, in which a portion of the TNCA salt is dissolved and the remainder is suspended. The preparation may contain 15-1000 mg of TNCA per ml as the salts of lysine or arginine. The body of the preparation may consist of distilled deionized water into which a portion of the salt is dissolved, and a water-miscible vehicle which is used as the supporting medium for the suspended TNCA salt. This formulation would also contain sodium chloride, sodium hydroxide, and a phosphate buffer as well as a suspending agent, a flavor, and a color.
- Another pharmaceutically acceptable liquid oral dosage form containing TNCA may also be prepared as an emulsion. The preparation may contain 15-1000 mg of TNCA per ml as the salts of lysine or arginine. The body of the preparation may consist of distilled deionized water and a vegetable oil properly emulsified with an emulsifying agent such as lecithin, pluronics, tweens, brijs, or arlacels, etc., as needed to produce a stable W/O emulsion of the water solution of the TNCA salt in the external oil phase. Also included may be sodium chloride, sodium hydroxide, phosphate buffer, preservative, humectant, flavor and color.
- Liquid oral dosage forms may offer advantages in certain patients and in certain applications. Patients unable to swallow large solid dosage forms would be particularly good candidates for a liquid dosage form. Liquid dosage forms may also allow larger amounts of drug to be administered in a manner that promotes patient compliance.
- It is also contemplated that a liquid dosage form may be used parenterally (by injection) either by I.V., S.C. or I.M. In the case of an injectable or parenteral liquid dosage form, one ml of solution may contain, in part, 15-1000 mg of TNCA as the salt of lysine or arginine. Also contained in the solution would be a salt such as sodium chloride for the purpose of achieving isotonicity; sodium hydroxide for adjustment of pH as needed (preferably to within the range 6 - 8); phosphate buffer; a preservative if needed; and U.S.P. Water For Injection.
- The following are specific exemplifications within the formulations of Examples 9 to 12.
-
Injectable (I.V., I.M., S.C.) - Single Dose TNCA 400 mg l-lysine 328 mg sodium chloride, U.S.P. 5 mg sodium hydroxide, U.S.P. 0.1 mg phosphate buffer (pH 7.0) 0.5 ml water for injection, U.S.P. q.s.a.d. 5.0 ml -
Injectable - Multiple Dose TNCA 400 mg l-lysine 328 mg sodium chloride, U.S.P. 5 mg sodium hydroxide, U.S.P. 0.1 mg phosphate buffer (pH 7.0) 0.5 ml Thimerosol 0.05 mg water for injection, U.S.P. q.s.a.d. 5.0 ml -
Oral Solution TNCA 600 mg l-arginine 586.5 mg sodium chloride, U.S.P. 2.0 mg sodium hydroxide, U.S.P. 0.2 mg potassium sorbate, U.S.P. 0.05 mg phosphate buffer (pH 7.0) 3.0 ml glycerine, U.S.P. 100 mg saccharin sodium, U.S.P. 0.5 mg natural strawberry flavor 0.05 ml FD&C Red #40 0.0001mg distilled deionized water q.s.a.d. 10.0 ml
Claims (8)
- A water-soluble compound selected from the lysine and arginine salts of thionapthene-2-carboxylic acid (TNCA).
- A method for making a compound as claimed in claim 1 which comprises mixing thionapthene-2-carboxylic acid with a solution of the salt-forming base.
- A method as claimed in claim 2 wherein the base is lysine and it is dissolved in a suitable solvent.
- A method as claimed in claim 3 wherein the solvent is an alcohol.
- A method as claimed in claim 4 wherein the TNCA is in solution in an alcohol prior to mixing with the salt-forming base.
- A method for preparing an aqueous solution of the lysine or arginine salt of thionapthene-2-carboxylic acid which comprises mixing the solid acid in an aqueous medium with lysine or arginine whereby an aqueous solution of the lysine or arginine salt is formed in situ.
- A pharmaceutical composition comprising a compound as claimed in claim 1.
- A pharmaceutical composition suitable for oral administration comprising an aqueous solution of a compound as claimed in claim 1.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT87307807T ATE70272T1 (en) | 1986-09-03 | 1987-09-03 | WATER-SOLUBLE SALTS OF THIONAPHTHENE-2CARBONS|URE. |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US90338586A | 1986-09-03 | 1986-09-03 | |
US903385 | 1986-09-03 | ||
US8684887A | 1987-08-19 | 1987-08-19 | |
US86848 | 1998-05-29 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0259168A1 EP0259168A1 (en) | 1988-03-09 |
EP0259168B1 true EP0259168B1 (en) | 1991-12-11 |
Family
ID=26775215
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP87307807A Expired - Lifetime EP0259168B1 (en) | 1986-09-03 | 1987-09-03 | New water-soluble salts of thionapthene-2-carboxylic acid |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0259168B1 (en) |
CA (1) | CA1327807C (en) |
DE (1) | DE3775147D1 (en) |
ES (1) | ES2037722T3 (en) |
FR (1) | FR2603281B1 (en) |
IT (1) | IT1218161B (en) |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4101668A (en) * | 1977-05-10 | 1978-07-18 | Bristol-Myers Company | Antiosteoporotic agents |
JPS59197446A (en) * | 1983-04-26 | 1984-11-09 | Mitsui Petrochem Ind Ltd | Polyolefin composition |
-
1987
- 1987-09-02 IT IT48347/87A patent/IT1218161B/en active
- 1987-09-02 FR FR8712216A patent/FR2603281B1/en not_active Expired - Fee Related
- 1987-09-02 CA CA000545947A patent/CA1327807C/en not_active Expired - Fee Related
- 1987-09-03 EP EP87307807A patent/EP0259168B1/en not_active Expired - Lifetime
- 1987-09-03 ES ES198787307807T patent/ES2037722T3/en not_active Expired - Lifetime
- 1987-09-03 DE DE8787307807T patent/DE3775147D1/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
FR2603281A1 (en) | 1988-03-04 |
IT1218161B (en) | 1990-04-12 |
DE3775147D1 (en) | 1992-01-23 |
IT8748347A0 (en) | 1987-09-02 |
CA1327807C (en) | 1994-03-15 |
EP0259168A1 (en) | 1988-03-09 |
ES2037722T3 (en) | 1993-07-01 |
FR2603281B1 (en) | 1993-12-03 |
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